Friend or foe? How the immune system copes with the gut microbiotica

The job of the human immune system is to destroy pathogens. Using a combination of quick, immediate responses (the innate immune system) and long-term memory (the adaptive immune system) in humans the cells of the immune system are perfectly primed to seek out any cells that are Other (i.e not Self) and kill them.

Which leads to a slight problem, because rather a lot of the cells within your body are 'Other' cells, and their existence is vital to your health. Within your stomach, and your respiratory tract, live a number of commensal bacteria, friendly and harmless bugs that can survive quite happily inside you and help to fight against incoming pathogenic bacteria. Stripping away the bacteria in the gut (i.e by going on a course of very strong antibiotics) leads to all kinds of problems including digestive problems and, once the antibiotics have finished, increased risk of disease-causing bacteria invading the now bacteria-free stomach.

In fact several notable yoghurt making companies are making a lot of money by selling you drinks with bacteria in them. They reassure you that the bacteria aren't dangerous, which is all well and good, but they never quite explain why the ingestion of many bacteria doesn't cause your immune system to have a panic attack.

A new review in Nature looks at the interactions between the gut microbiome and the immune system. The 'gut microbiome' is the collection of bacteria that start colonising the inside of your intestines soon after birth, both from your mother, and from the general environment. It's helpful here to remember that technically your intestinal tract isn't actually inside your body. There's an open tube right the way from your mouth to your arse (for want of a better word...) so the body has a tendency to treat bacteria living there in similar ways to the bacteria living on your skin, by using barriers to keep them out.

However there still is a trade off. The cells that make up the intestinal walls still need to be able to respond to bacteria, and the commensal bacteria still need to be contained. A non-regulated population of bacteria will simply keep growing until all available space is filled (and all nutrients eaten), and this does not happen within the gut.

Starting with the innate immune system which works by recognising molecules found in all pathogens (called PAMPs) these are recognised by human cells using receptors called TLRs (Toll-like receptors - long story) and lead to a signalling cascade that result in a huge number of cytokines and other inflammatory agents being released to kill the bacteria. In the gut this wouldn't just lead to the massive slaughter of the microbiome, but also to a huge amount of damage to the surrounding human cells. Enough exposure to microbial elements such as lipopolysacharrides can downregulate this response; the lipopolysacharrides (which are in the bacteria cell wall) down-regulate one of the key components of the signalling system, a molecule called IRAK1. This prevents the cell from mounting a response to the bacteria. For those that want scientific details, check out the diagram below (image from the reference):

The adaptive immune system is more complex. In normal situations it works by taking a small sample of the bacteria back to the lymph nodes and preparing a specific immune response against it. Special immune cells (B cells) are then made which will kill the specific bacteria, with the help of T cells, which also act as a memory of the threat and the correct response. The B cells are then sent to the point of infection and secrete antibodies which clump the bacteria into groups and recruit other factors to kill them.

This still mostly happens in the case of the gut microbiome, the B cells release the antibody IgA which diffuses out into the intestinal tract and traps the bacteria in the mucus layer. However the bacteria are able to strike back, not by targeting the B cells, but the T cells. There are many different forms of T cells, and by secreting certain chemicals the bacteria can encourage the formation of T-regulatory cells which encourage tolerance towards both commensal bacteria and molecules in food.

So it seems to be not so much a relationship of mututal tolerence and understanding, but more like a sort of uneasy standoff. Bacteria are still being killed to stop them spreading, but are holding off the immune systeme enough to maintain a steady population. In return, the immune system is still there and active, but not active enough to cause any serious damage to either the microbiotica or the surrounding human cells.

7 comments:

Nice post! I never dare to tackle posts on the immune system, as it can get complicated so fast, but you've managed to keep it clear and concise :).

One question though (sorry): so it is the overexposure to lipopolysacharrides that triggers the innate immune cells to become tolerant for the commensal bacteria? Little amounts of LPS in other parts of the body would still trigger the innate immune system, if I understand it correctly?

@Lucas: hi! It took more time than usual to write this post, including several check-ups with my medic-fiancé to try and get the immune system as correct yet non-technical as possible!

It wasn't clear just what affect the LPSs were having in terms of stopping the immune system, but it is true that they still do switch it on in other places in the body. I would guess that the response is just dampened in the stomach.

Thanks so much for this, Labrat. The immune system is something that I do not understand well enough. My brother has lupus and I always *intend* to look up why the body recognizes our bacteria as acceptable but can consider our own bodies unacceptable. Maybe after reading this I'll actually dive into the literature...

@Lucas: LPS tolerance has been studied for ages and there are a bunch of negative regulatory loops that turn off signaling and degrade the proteins involved intracellularly - but those only affect individual cells that have been exposed (in other words, tolerance won't disseminate throughout the body). The thing is, the innate immune cells of the gut can still respond to LPS from pathogens, so there's clearly something else going on.

@Hannah- That's going to be long literature search, but I'm going to be writing something up on autoimmunity in the near future if you're interested. In a nutshell, the adaptive immune system has a bunch of systems in place to make sure it's tolerant of your own tissue, but in people with autoimmunity, those control systems break down.

Yes, lipopolysaccharides from Gram-negative bacteria act as endotoxins and do elicit an extremely potent inflammatory response in humans. Indeed, Gram-negative septicaemia is life-threatening. Also, interestingly, lipopolysaccharides are released from lysed bacteria, which is one of the reasons treating E. coli 0157 with antibiotics can result in haemolytic-uraemic syndrome.

However, there is a lot of variability of lipopolysaccharide molecules between different bacterial strains, and some of them actually antagonise toll-like receptors, which may explain how some strains of bacteria avoid eliciting an acute inflammatory response.

Furthermore, humans produce an enzyme in the gut called alkaline phosphatase, which removes the phosphate groups from lipopolysaccharides, which may be another mechanism through which acute inflammatory responses to bacteria in the gut are regulated.

There is a condition called small bowel bacterial overgrowth, where excess commensal bacteria colonise the small bowel lumen. However, this is often due to a failure of barrier mechanisms, such as loss of bowel motility, increased stomach pH due to use of proton pump inhibitors, and blind loops being caused by diverticula or surgery.